Alteration in facial skin blood flow during acute exposure to -10 and -30° head-down tilt in young human volunteers.

NEW FINDINGS: What is the central question of this study? Facial skin blood flow (SBF) might increase during head-down tilt (HDT). However, the effect of HDT on facial SBF remains controversial. In addition, the changes in facial SBF in the cheek (cheek SBF) during a steeper angle of HDT (>-12° HDT) have not been investigated. What is the main finding and its importance? This study showed that cheek SBF decreased during -30° HDT, alongside increased vascular resistance. Furthermore, vascular impedance was suggested to be elevated, accompanied by an increased hydrostatic pressure gradient caused by HDT. Constriction of the facial skin vascular bed and congestion of venous return owing to the steep angle of HDT can decrease facial SBF. ABSTRACT: Head-down tilt (HDT) has been used to simulate microgravity in ground-based studies and clinical procedures including the Trendelenburg position or in certain surgical operations. Facial skin blood flow (SBF) might be altered by HDT, but the effect of a steeper angle of HDT (>-12° HDT) on facial SBF remains unclear. We examined alterations in facial SBF in the cheek (cheek SBF) using two different angles (-10 and -30°) of HDT and lying horizontal (0°) in a supine position for 10 min, to test the hypothesis that cheek SBF would increase with a steeper angle of HDT. Cheek SBF was measured continuously by laser Doppler flowmetry. Cheek skin vascular resistance and the pulsatility index of cheek SBF were calculated to assess the circulatory effects on the facial skin vascular bed in the cheek. Cheek SBF decreased significantly during -30° HDT. In addition, the resistance in cheek SBF increased significantly during -30° HDT. The pulsatility index of cheek SBF increased during both -10 and -30° HDT. Contrary to our hypothesis, cheek SBF decreased during -30° HDT along with increased skin vascular resistance. Vascular impedance, estimated by the pulsatility index in the cheek SBF, was elevated during both -10 and -30° HDT, and elevated vascular impedance would be related to increased hydrostatic pressure induced by HDT. Skin vascular constriction and venous return congestion would be induced by -30° HDT, leading to deceased cheek SBF. The present study suggested that facial SBF in the cheek decreased during acute exposure to a steep angle of HDT (∼-30° HDT).

Cold-induced vasodilation in abstinent smokers with and without a 12-hour nicotine patch.

This study was designed to identify the effects of a 12-h nicotine patch administration on cold induced vasodilation (CIVD) in healthy young chronic smokers following 16 h of abstinence from smoking. Two laser Doppler probes and temperature thermocouples were placed on the dorsal part of the distal phalanx of the middle and ring fingers of 7 smokers (>12 cigarettes/day). Following 16 h of abstinence from smoking, smokers were tested with and without administration of a 21 mg transdermal nicotine patch (NicoDerm® ). Each participant's right hand was immersed in cold (~5°C) water for 40 min. Cutaneous vascular conductance (CVC) was calculated from non-invasive arterial finger blood pressure and skin blood flow and expressed as a percentage of peak CVC observed during hand skin heating to 44°C. For comparison purposes, the CIVD response of a non-smoking cohort without nicotine patch (n = 10) was also examined. Baseline CVC was similar in smokers and non-smokers (27.8 ± 12.6 CVC % peak). The initial vasoconstriction during cold-water immersion decreased skin blood flow to 4.0 ± 3.9 CVC % peak in both smokers and non-smokers. The onset of CIVD in smokers (4.5 ± 1.5 min) was delayed compared to non-smoker (3.3 ± 0.8 min, p < .05). The area under the CVC %peak-time curve during cold-water immersion averaged 1250 ± 388 CVC %peak · min in non-smokers which was larger (p < .05) than smokers with or without nicotine (789 ± 542 and 862 ± 517 CVC %peak · min, respectively). Chronic smoking impaired the CIVD response to cold-water immersion of the hand; however, the impaired CIVD response in 16 h of abstinence from smoking was not influenced by application of a 21 mg transdermal nicotine patch.

Vascular reactivity of cutaneous circulation to brief compressive stimuli, in the human forearm.

PURPOSE: A brief compressive stimulus is known to induce a rapid hyperemia in skeletal muscles, considered to contribute to the initial phase of functional hyperemia. Whether the same mechano-sensitivity characterizes the cutaneous circulation is debated. This study aims to investigate whether a rapid hyperemic response to compressive stimuli is also expressed by skin blood flow in humans. METHODS: In 12 subjects, brief compressive stimuli were delivered to the forearm at varying pressures/durations (50/2, 100/2, 200/2, 200/1, 200/5 mmHg/s); the sequence was randomized and repeated with the arm above and below heart level. Laser Doppler flowmetry technique was used to monitor skin blood flow. The response was described in terms of peak skin blood flow normalized to baseline (nSBFpeak), time-to-peak from the release of compression, and excess blood volume (EBV, expressed in terms of seconds of basal flow, s-bf) received during the response. RESULTS: The results consistently evidenced the occurrence of a compression-induced hyperemic response, with nSBFpeak = 2.9 ± 1.1, EBV = 17.0 ± 6.6 s-bf, time-to-peak = 7.0 ± 0.7 s (200 mmHg, 2 s, below heart level). Both nSBFpeak and EBV were significantly reduced (by about 50%) above compared to below heart level (p < 0.01). In addition, EBV slightly increased with increasing pressure (p < 0.05) and duration (p < 0.01) of the stimulus. CONCLUSIONS: For the first time, the rapid dilatator response to compressive stimuli was demonstrated in human cutaneous circulation. The functional meaning of this response remains to be elucidated.

Interactions of mild hypothermia and hypoxia on finger vasoreactivity to local cold stress.

We examined the interactive effects of mild hypothermia and hypoxia on finger vasoreactivity to local cold stress. Eight male lowlanders performed, in a counterbalanced order, a normoxic and a hypoxic (partial pressure of oxygen: ~12 kPa) hand cold provocation (consisting of a 30-min immersion in 8°C water), while immersed to the chest either in 21°C [cold trials; 0.5°C fall in rectal temperature (Trec) from individual preimmersion values], or in 35.5°C water, or while exposed to 27°C air. The duration of the trials was kept constant in each breathing condition. Physiological (Trec, skin temperature, cutaneous vascular conductance, oxygen uptake) and perceptual (thermal sensation and comfort, local pain, affective valence) reactions were monitored continually. Hypoxia accelerated the drop in Trec by ~14 min (P = 0.06, d = 0.67). In the air-exposure trials, hypoxia did not alter finger perfusion during the local cooling, whereas it impaired the finger rewarming response following the cooling (P < 0.01). During the 35.5°C immersion, the finger vasomotor tone was enhanced, especially in hypoxia (P = 0.01). Mild hypothermia aggravated finger vasoconstriction instigated by local cooling (P < 0.01), but the response did not differ between the two breathing conditions (P > 0.05). Hypoxia tended to attenuate the sensation of coldness (P = 0.10, r = 0.40) and thermal discomfort (P = 0.09, r = 0.46) in the immersed hand. Both in normoxia and hypoxia, the whole body thermal state dictates the cutaneous vasomotor reactivity to localized cold stimulus.

Painless local pressure application to test microvascular reactivity to ischemia.

BACKGROUND: Forearm cutaneous blood flux (CBF) measurement with post-occlusive reactive hyperemia (PORH) is uncomfortable and may not be devoid of risks. We aimed to investigate post-compression reactive hyperemia (PCRH) with a custom-made indenter that was designed to be easily used routinely by inexperienced observers. METHODS: Medical students evaluated PCRH with 1- to 4-min pressure applications of 16 to 34 kPa and PORH with 3-min forearm cuff occlusion using laser speckle contrast imaging in 15 healthy volunteers. Participants were asked to quantify their discomfort with a visual analogue scale (VAS) of 10 cm. Total ischemia (ISCH) was quantified by the product of CBF during ischemia and ischemia duration (min). We subtracted the CBF changes in the skin from a reference ipsilateral (PCRH) or contralateral (PORH) non-stimulated area. RESULTS: The average VAS was 1.0 for PCRH vs. 6.0 for PORH (p < 0.001). A strong linear relationship between ISCH and peak PCRH (r2 = 0.915, p < 0.001) was noted. Peak PORH values (63.9 laser perfusion units (LPU)) were significantly lower than all values of the 3-min PCRH (72.6 LPU), including the one obtained with 16 kPa. CONCLUSION: Inexperienced observers could test microvascular reactivity with PCRH without inducing the discomfort that is typically experienced with PORH. Further, PCRH elicits a higher peak response to ischemia compared with PORH. This extremely simple method could influence a broad spectrum of routine cutaneous microcirculation investigations, especially when a painful approach is particularly inadequate or if the patient is fragile. CLINICAL TRIAL REGISTRATION: NCT02861924.

Effects of insulin analogs as an add-on to metformin on cutaneous microcirculation in type 2 diabetic patients.

BACKGROUND: A single insulin injection was shown to improve microcirculatory blood flow. Our aim was to examine the effects of 4weeks of insulin therapy by three randomly assigned insulin analog regimens (Detemir, Aspart, and their combination) on cutaneous blood flow (CBF) and microcirculatory endothelial function as an add-on to metformin in type 2 diabetic patients poorly controlled on oral antidiabetic treatment. METHODS: Fourty-two type 2 diabetic patients with no history of cardiovascular disease in secondary failure to oral antidiabetic agents had CBF measurements before and after acetylcholine (Ach) iontophoretic administration. CBF measurements were performed at fasting and after a standardized breakfast during the post-prandial period. Before randomization (Visit 1, V1) during the tests, participants took only metformin. The same tests were repeated after 4weeks of insulin treatment (Visit 2, V2). RESULTS: Thirty-four patients had good quality recordings for both visits. During V1, CBF and CBF response to Ach increased in the post-prandial period. After 4weeks of insulin treatment, metabolic parameters improved. Compared to V1, CBF at fasting did not increase at V2 but there was an improvement in endothelial function at fasting after Ach iontophoresis, without difference across insulin regimens. Oxidative stress markers were not modified, and E-selectin and vascular cell adhesion molecule 1 levels decreased after insulin treatment, without differences between insulin groups. CONCLUSIONS: A strategy of improving glycemic control for 4weeks with insulin analogs improves microcirculatory endothelial reactivity and reduces endothelial biomarkers at fasting, whatever the insulin regimen used. Insulin therapy associated to metformin is able to improve fasting microvascular endothelial function even before complete metabolic control.

Measuring and quantifying skin sympathetic nervous system activity in humans.

Development of the technique of microneurography has substantially increased our understanding of the function of the sympathetic nervous system (SNS) in health and in disease. The ability to directly record signals from peripheral autonomic nerves in conscious humans allows for qualitative and quantitative characterization of SNS responses to specific stimuli and over time. Furthermore, distinct neural outflow to muscle (MSNA) and skin (SSNA) can be delineated. However, there are limitations and caveats to the use of microneurography, measurement criteria, and signal analysis and interpretation. MSNA recordings have a longer history and are considered relatively more straightforward from a measurement and analysis perspective. This brief review provides an overview of the development of the technique as used to measure SSNA. The focus is on the utility of measuring sympathetic activity directed to the skin, the unique issues related to analyzing and quantifying multiunit SSNA, and the challenges related to its interpretation.

Variations in body morphology explain sex differences in thermoeffector function during compensable heat stress.

NEW FINDINGS: What is the central question of this study? Can sex-related differences in cutaneous vascular and sudomotor responses be explained primarily by variations in the ratio between body surface area and mass during compensable exercise that elicits equivalent heat-loss requirements and mean body temperature changes across participants? What is the main finding and its importance? Mass-specific surface area was a significant determinant of vasomotor and sudomotor responses in men and women, explaining 10-48% of the individual thermoeffector variance. Nonetheless, after accounting for changes in mean body temperature and morphological differences, sex explained only 5% of that inter-individual variability. It was concluded that sex differences in thermoeffector function are morphologically dependent, but not sex dependent. Sex is sometimes thought to be an independent modulator of cutaneous vasomotor and sudomotor function during heat exposure. Nevertheless, it was hypothesized that, when assessed during compensable exercise that evoked equal heat-loss requirements across participants, sex differences in those thermoeffectors would be explained by variations in the ratio between body surface area and mass (specific surface area). To evaluate that possibility, vasomotor and sudomotor functions were assessed in 60 individuals (36 men and 24 women) with widely varying (overlapping) specific surface areas (range, 232.3-292.7 and 241.2-303.1 cm2  kg-1 , respectively). Subjects completed two trials in compensable conditions (28°C, 36% relative humidity) involving rest (20 min) and steady-state cycling (45 min) at fixed, area-specific metabolic heat-production rates (light, ∼135 W m-2 ; moderate, ∼200 W m-2 ). Equivalent heat-loss requirements and mean body temperature changes were evoked across participants. Forearm blood flow and vascular conductance were positively related to specific surface area during light work in men (r = 0.67 and r = 0.66, respectively; both P < 0.05) and during both exercise intensities in women (light, r = 0.57 and r = 0.69; and moderate, r = 0.64 and r = 0.68; all P < 0.05). Whole-body and local sweat rates were negatively related to that ratio (correlation coefficient range, -0.33 to -0.62; all P < 0.05) during both work rates in men and women. Those relationships accounted for 10-48% of inter-individual thermoeffector variance (P < 0.05). Furthermore, after accounting for morphological differences, sex explained no more than 5% of that variability (P < 0.05). It was concluded that, when assessed during compensable exercise, sex differences in thermoeffector function were largely determined morphologically, rather than being sex dependent.

Tissue Blood Volume Parameters Measured by Continuous-Wave and Spatially Resolved NIRS Show Different Changes During Prolonged Cycling Exercise.

Near-infrared spectroscopy (NIRS) shows two types of tissue blood volume (BV) parameters: the total hemoglobin concentration (cHb; assessed by continuous-wave NIRS) and the normalized tissue hemoglobin index (nTHI; evaluated by spatially resolved NIRS). This study was performed to investigate the differences between cHb and nTHI, estimated by calibration using acute reduction of BV at the onset of exercise. Seven active male volunteers (age: 22  ±  4 years) performed a prolonged (60-min) cycling exercise test at 65% or 70% of the peak oxygen uptake. During the tests, cHb and nTHI from the vastus lateralis muscle were monitored. The two parameters were expressed relative to the resting value of 100% and the minimum value of 0% at the onset of exercise. The value of cHb started to increase after arriving at the minimum value and continued until the end of exercise. Similar to cHb, nTHI increased acutely from the lowest level, but the parameter remained almost unchanged from ~5 min throughout the test. Therefore, the two parameters interacted significantly. Moreover, in comparison with the same exercise duration, cHb was significantly higher than nTHI from the 28th min to the end of the test. These results suggest that cHb and nTHI in working muscle are not synchronized during prolonged exercise, especially after ~30 min. The differences between the two BV parameters are likely partly attributable to other factors, such as the increase in skin blood flow.

Thermoregulatory responses to combined moderate heat stress and hypoxia.

OBJECTIVE: The aim of this study was to examine the cutaneous vascular and sudomotor responses to combined moderate passive heat stress and normobaric hypoxia. METHOD: Thirteen healthy young males, dressed in a water-perfused suit, underwent passive heating (Δcore temperature ~0.7°C) twice (Normoxia; 20.9% O2 and Hypoxia; 13% O2 ). Chest and forearm skin blood flow (SkBF; laser-Doppler flux) and sweat rate (SR; capacitance hygrometry), core (intestinal pill), and skin temperatures, were recorded. RESULTS: Hypoxia reduced baseline oxygen saturation (98±1 vs 89±6%, P<.001) and elevated chest (P=.03) and forearm SkBF (P=.03), and HR (64±9 vs 69±8 beats.min-1 , P<.01). During heating, mean body temperature (T¯BODY) thresholds for SkBF (P=.41) and SR (P=.28) elevations were not different between trials. The SkBF: T¯BODY linear sensitivity during the initial phase of heating was lower at the chest (P=.035) but not different at the forearm (P=.17) during hypoxia. With increasing levels of heating chest SkBF was not different (P=.55) but forearm SkBF was lower (P<.01) during hypoxia. Chest (P=.85) and forearm (P=.79) SR: T¯BODY linear sensitivities were not different between trials. CONCLUSION: While sudomotor responses and the initiation of cutaneous blood flow elevations are unaffected, hypoxia differentially effects regional SkBF responses during moderate passive heating.

Locus coeruleus noradrenergic innervation of the amygdala facilitates alerting-induced constriction of the rat tail artery.

The amygdala, innervated by the noradrenergic locus coeruleus, processes salient environmental events. α2-adrenoceptor-stimulating drugs (clonidine-like agents) suppress the behavioral and physiological components of the response to salient events. Activation of sympathetic outflow to the cutaneous vascular bed is part of the physiological response to salience-mediated activation of the amygdala. We have determined whether acute systemic and intra-amygdala administration of clonidine, and chronic immunotoxin-mediated destruction of the noradrenergic innervation of the amygdala, impairs salience-related vasoconstrictor episodes in the tail artery of conscious freely moving Sprague-Dawley rats. After acute intraperitoneal injection of clonidine (10, 50, and 100 µg/kg), there was a dose-related decrease in the reduction in tail blood flow elicited by alerting stimuli, an effect prevented by prior administration of the α2-adrenergic blocking drug idazoxan (1 mg/kg ip or 75 nmol bilateral intra-amygdala). A dose-related decrease in alerting-induced tail artery vasoconstriction was also observed after bilateral intra-amygdala injection of clonidine (5, 10, and 20 nmol in 200 nl), an effect substantially prevented by prior bilateral intra-amygdala injection of idazoxan. Intra-amygdala injection of idazoxan by itself did not alter tail artery vasoconstriction elicited by alerting stimuli. Intra-amygdala injection of saporin coupled to antibodies to dopamine-ß-hydroxylase (immunotoxin) destroyed the noradrenergic innervation of the amygdala and the parent noradrenergic neurons in the locus coeruleus. The reduction in tail blood flow elicited by standardized alerting stimuli was substantially reduced in immunotoxin-treated rats. Thus, inhibiting the release of noradrenaline within the amygdala reduces activation of the sympathetic outflow to the vascular beds elicited by salient events.

Brown adipose tissue thermogenesis contributes to emotional hyperthermia in a resident rat suddenly confronted with an intruder rat.

Body temperature increases when individuals experience salient, emotionally significant events. There is controversy concerning the contribution of nonshivering thermogenesis in brown adipose tissue (BAT) to emotional hyperthermia. In the present study we compared BAT, core body, and brain temperature, and tail blood flow, simultaneously measured, to determine whether BAT thermogenesis contributes to emotional hyperthermia in a resident Sprague-Dawley rat when an intruder rat, either freely-moving or confined to a small cage, is suddenly introduced into the cage of the resident rat for 30 min. Introduction of the intruder rat promptly increased BAT, body, and brain temperatures in the resident rat. For the caged intruder these temperature increases were 1.4 ± 0.2, 0.8 ± 0.1, 1.0 ± 0.1°C, respectively, with the increase in BAT temperature being significantly greater (P < 0.01) than the increases in body and brain. The initial 5-min slope of the BAT temperature record (0.18 ± 0.02°C/min) was significantly greater (P < 0.01) than the corresponding value for body (0.10 ± 0.01°C/min) and brain (0.09 ± 0.02°C/min). Tail artery pulse amplitude fell acutely when the intruder rat was introduced, possibly contributing to the increases in body and brain temperature. Prior blockade of ß3 adrenoceptors (SR59230A 10 mg/kg ip) significantly reduced the amplitude of each temperature increase. Intruder-evoked increases in BAT temperature were similar in resident rats maintained at 11°C for 3 days. In the caged intruder situation there is no bodily contact between the rats, so the stimulus is psychological rather than physical. Our study thus demonstrates that BAT thermogenesis contributes to increases in body and brain temperature occurring during emotional hyperthermia.

Reduced brown adipose tissue thermogenesis during environmental interactions in transgenic rats with ataxin-3-mediated ablation of hypothalamic orexin neurons.

Thermogenesis in brown adipose tissue (BAT) contributes to substantial increases in body temperature evoked by threatening or emotional stimuli. BAT thermogenesis also contributes to increases in body temperature that occur during active phases of the basic rest-activity cycle (BRAC), as part of normal daily life. Hypothalamic orexin-synthesizing neurons influence many physiological and behavioral variables, including BAT and body temperature. In conscious unrestrained animals maintained for 3 days in a quiet environment (24-26°C) with ad libitum food and water, we compared temperatures in transgenic rats with ablation of orexin neurons induced by expression of ataxin-3 (Orx_Ab) with wild-type (WT) rats. Both baseline BAT temperature and baseline body temperature, measured at the onset of BRAC episodes, were similar in Orx_Ab and WT rats. The time interval between BRAC episodes was also similar in the two groups. However, the initial slopes and amplitudes of BRAC-related increases in BAT and body temperature were reduced in Orx_Ab rats. Similarly, the initial slopes and amplitudes of the increases in BAT temperatures induced by sudden exposure to an intruder rat (freely moving or confined to a small cage) or by sudden exposure to live cockroaches were reduced in resident Orx_Ab rats. Constriction of the tail artery induced by salient alerting stimuli was also reduced in Orx_Ab rats. Our results suggest that orexin-synthesizing neurons contribute to the intensity with which rats interact with the external environment, both when the interaction is "spontaneous" and when the interaction is provoked by threatening or salient environmental events.

Effect of heat-killed Lactobacillus brevis SBC8803 on cutaneous arterial sympathetic nerve activity, cutaneous blood flow and transepidermal water loss in rats.

AIM: To evaluate the efficacy of the effects of heat-killed Lactobacillus brevis SBC8803 (HK-SBC8803) on the standard physiological markers of skin health of cutaneous arterial sympathetic nerve activity (CASNA), cutaneous blood flow and transepidermal water loss (TEWL) and to determine whether SBC8803 targets serotonin 5-HT3 receptors in rats. METHODS AND RESULTS: A set of three experiments were conducted to examine the effects of SBC8803 on CASNA, cutaneous blood flow and TEWL using Wistar and hairless rats. Two additional experiments further attempted to determine whether HK-SBC8803 was targeting the serotonin 5-HT3 receptors by pretreatment with the 5-HT3 antagonist granisetron. Administration of HK-SBC8803 in the first three experiments caused marked inhibition of CASNA and significant elevation of cutaneous blood flow under urethane anaesthesia as well as significant decrease in TEWL on the dorsal skin of conscious hairless rats. Pretreatment with granisetron decreased the effects of HK-SBC8803 on CASNA and cutaneous blood flow. CONCLUSIONS: These findings suggest that HK-SBC8803 reduces CASNA, increases cutaneous blood flow and decreases TEWL and that 5-HT3 receptors may be involved in CASNA and cutaneous blood flow responses. SIGNIFICANCE AND IMPACT OF THE STUDY: HK-SBC8803 could be a useful substance in the treatment/prevention of skin problems, specifically chapped or dry skin.

Mucopolysaccharide polysulfate increases local skin blood volume through nitric oxide production.

BACKGROUND: Mucopolysaccharide polysulfate (MPS) is widely used as an active ingredient in topical preparations for the treatment of asteatosis and blood flow disorders. Although topical MPS products can increase cutaneous blood flow (CBF), the underlying mechanism remains unclear. OBJECTIVE: In this study, we aimed to elucidate how MPS increases CBF. We investigated the association of nitric oxide (NO), a powerful mediator associated with increased local blood volume, with the blood flow-accelerating action of MPS in mice. In addition, we verified the effects of MPS on NO production in different skin cell types, such as keratinocytes (KCs), endothelial cells (ECs), and dermal fibroblasts (DFs). METHODS: We used raster-scanning optoacoustic imaging mesoscopy to observe in vivo changes in the skin blood volume. NO production was determined in each cell using an NO indicator. An enzyme-linked immunoassay was used to measure the phosphorylated nitric oxide synthase (NOS) levels in ECs, DFs, and KCs in the presence or absence of MPS. RESULTS: Topical application of MPS increased the skin blood volume in mice, and this increase was abolished through the addition of NOS inhibitors. MPS promoted the dose-dependent production of NO in various cells, which caused alterations in the phosphorylation state of NOS. CONCLUSION: Our findings demonstrate that MPS promotes an increase in skin blood volume and NO production in various skin cell types. These results suggest that MPS can potentially accelerate CBF through the NO biosynthesis pathway in different skin cell types.

A Single Bout of Remote Ischemic Preconditioning Suppresses Ischemia-Reperfusion Injury in Asian Obese Young Men.

Remote ischemic preconditioning (RIPC) has been shown to minimize subsequent ischemia-reperfusion injury (IRI), whereas obesity has been suggested to attenuate the efficacy of RIPC in animal models. The primary objective of this study was to investigate the effect of a single bout of RIPC on the vascular and autonomic response after IRI in young obese men. A total of 16 healthy young men (8 obese and 8 normal weight) underwent two experimental trials: RIPC (three cycles of 5 min ischemia at 180 mmHg + 5 min reperfusion on the left thigh) and SHAM (the same RIPC cycles at resting diastolic pressure) following IRI (20 min ischemia at 180 mmHg + 20 min reperfusion on the right thigh). Heart rate variability (HRV), blood pressure (SBP/DBP), and cutaneous blood flow (CBF) were measured between baseline, post-RIPC/SHAM, and post-IRI. The results showed that RIPC significantly improved the LF/HF ratio (p = 0.027), SBP (p = 0.047), MAP (p = 0.049), CBF (p = 0.001), cutaneous vascular conductance (p = 0.003), vascular resistance (p = 0.001), and sympathetic reactivity (SBP: p = 0.039; MAP: p = 0.084) after IRI. However, obesity neither exaggerated the degree of IRI nor attenuated the conditioning effects on the measured outcomes. In conclusion, a single bout of RIPC is an effective means of suppressing subsequent IRI and obesity, at least in Asian young adult men, does not significantly attenuate the efficacy of RIPC.

The effect of glucagon on local subcutaneous blood flow in non-diabetic volunteers; a proof-of-concept study.

INTRODUCTION: Glucagon and insulin are the two most important hormones in glucose metabolism and have been incorporated in the dual-hormonal artificial pancreas, a device for automated glucose regulation for people with diabetes type 1. Currently the subcutis is the preferred site of hormone delivery for insulin-only as well as dual-hormonal artificial pancreas systems. The delay in glucose-lowering effect after subcutaneous injection of insulin is substantial, in contrast to the elevation of blood glucose values after subcutaneously injected glucagon which is occurs shortly after injection. We hypothesize that this is caused by properties of glucagon and have investigated the vasodilative effect of glucagon on subcutaneous blood flow in this proof-of-concept study. METHODS: Twenty-two volunteers received subcutaneous injections of 0.1 mg and 0.01 mg glucagon, and saline on the abdomen. Blood flow was measured by a laser doppler blood flowmeter for 35 min after injections. RESULTS: Injection of 0.1 mg glucagon resulted in a significant increase in blood flow compared with baseline blood flow for all time intervals. Significant increase was also observed after the 0.01 mg glucagon injection, except between two- and five-min post injection. The inter-individual variance was large and a third of the subjects did not show an apparent increase in local subcutaneous blood flow after the 0.1 mg glucagon injection. CONCLUSION: This proof-of-concept study shows that micro-boluses of glucagon increases local subcutaneous blood flow on the abdomen of non-diabetic subjects. However, the vasodilative effect of glucagon is not observed in all subjects. The trial was not registered to protect intellectual property rights.

Vascular endothelium as a target tissue for short-term exposure to low-frequency noise that increases cutaneous blood flow.

Harmful health effects of exposure to low-frequency noise (LFN) defined as noise with frequencies at ≤100 Hz on the circulatory system have been a concern. However, there has been no study on the effects of exposure to LFN on the circulatory system with consideration of its frequencies and decibels. In this study, the effects of short-term exposure to broad-band LFNs and their pure-tone components (pure-tone LFNs) on cutaneous blood flow in the extremities including the hands were investigated. In our fieldwork study, we first sampled some kinds of common broad-band LFNs. Our human study then showed that broad-band LFN with a narrower frequency range more strongly increased cutaneous blood flow than did broad-band LFN with a wider frequency range. Pure-tone LFNs of 70-100 Hz at ≤85 dB(Z), but not pure-tone LFNs exceeding 100 Hz, further increased levels of cutaneous blood flow. Our wavelet-transform spectrum analysis of cutaneous blood flow next revealed that the nitric oxide (NO)-dependent and -independent vascular activities of the vascular endothelium were specifically increased by exposure to pure-tone LFN. Our animal study again indicated that exposure to pure-tone LFN increased cutaneous blood flow in mice with impairments of bilateral inner ears as well as cutaneous blood flow in control mice, suggesting a limited effect of inner ear function on the LFN-mediated increase in cutaneous blood flow. The NO-dependent suppressive effect of pure-tone LFN on cutaneous blood flow was confirmed by inhibition of vascular endothelial activity through intravenous injection of an NO inhibitor in wild-type mice. Taken together, the results of this study demonstrated that the vascular endothelium is a target tissue of LFN and that NO is an effector of the LFN-mediated increase in cutaneous blood flow. Since improvement of peripheral circulation could generally promote human health, short-term exposure to LFN may be beneficial for health.

The Efficacy of Exercise Training for Cutaneous Microvascular Reactivity in the Foot in People with Diabetes and Obesity: Secondary Analyses from a Randomized Controlled Trial.

It is unclear if cutaneous microvascular dysfunction associated with diabetes and obesity can be ameliorated with exercise. We investigated the effect of 12-weeks of exercise training on cutaneous microvascular reactivity in the foot. Thirty-three inactive adults with type 2 diabetes and obesity (55% male, 56.1 ± 7.9 years, BMI: 35.8 ± 5, diabetes duration: 7.9 ± 6.3 years) were randomly allocated to 12-weeks of either (i) moderate-intensity continuous training [50−60% peak oxygen consumption (VO2peak), 30−45 min, 3 d/week], (ii) low-volume high-intensity interval training (90% VO2peak, 1−4 min, 3 d/week) or (iii) sham exercise placebo. Post-occlusive reactive hyperaemia at the hallux was determined by laser-Doppler fluxmetry. Though time to peak flux post-occlusion almost halved following moderate intensity exercise, no outcome measure reached statistical significance (p > 0.05). These secondary findings from a randomised controlled trial are the first data reporting the effect of exercise interventions on cutaneous microvascular reactivity in the foot in people with diabetes. A period of 12 weeks of moderate-intensity or low-volume high-intensity exercise may not be enough to elicit functional improvements in foot microvascular reactivity in adults with type 2 diabetes and obesity. Larger, sufficiently powered, prospective studies are necessary to determine if additional weight loss and/or higher exercise volume is required.

Aging increases circulating BH2 without modifying BH4 levels and impairs peripheral vascular function in healthy adults.

Little is known about the mechanisms of aging on vascular beds and its relationship with tetra and di-hydrobiopterin (BH4 and BH2) levels. This observational clinical study analyzed the impact of aging on plasma and platelet biopterins, cutaneous blood flow (CBF), and coronary flow reserve (CFR) in healthy adults. The study enrolled healthy adults in 3 age groups: 18-30, 50-59, and 60-70 years (n = 25/group). Biopterins were assessed by LC-MS/MS using newly defined pre-analytical conditions limiting BH4 oxidation and improving long-term stability. CBF was measured by Laser Speckle Contrast Imaging coupled with acetylcholine-iontophoresis and CFR by adenosine stress cardiac magnetic resonance. In healthy adults, aging (60-70 years vs 18-30 years) significantly increased platelet BH2 (+75%, P = 0.033) and BH2 + BH4 (+31%, P = 0.033), and to a lesser extent plasma BH2 (+29%, P = 0.009) without affecting BH4 and BH4/BH2. Simultaneously, CBF was decreased (-23%, P = 0.004) but not CFR, CBF being inversely correlated with platelet BH2 (r = -0.42, P = 0.001) and BH2 + BH4 (r = -0.41, P = 0.002). The proportion of adults with abnormal platelet BH2 increased with age (+28% in 60-70y). These abnormal BH2 levels were significantly associated with reduced CBF and CFR (-16%, P = 0.03 and -26%, P = 0.02). In conclusion, our study showed that age-related peripheral endothelial dysfunction was associated with an increase in circulating BH2 without decreasing BH4, the effect being more marked in platelets, the most relevant blood compartment to assess biopterin bioavailability. Peripheral but not coronary vascular function is progressively impaired with aging in healthy adults. All these findings support biopterins as therapeutic targets to improve vascular function.